CDDO-Methyl Ester Delays Breast Cancer Development in Brca1-Mutated Mice

Department of Medicine, Dartmouth Medical School, Hanover, NH 03755, USA.
Cancer Prevention Research (Impact Factor: 4.44). 09/2011; 5(1):89-97. DOI: 10.1158/1940-6207.CAPR-11-0359
Source: PubMed

ABSTRACT The breast cancer-associated gene 1 (BRCA1) is the most frequently mutated tumor suppressor gene in familial breast cancers. Mutations in BRCA1 also predispose to other types of cancers, pointing to a fundamental role of this pathway in tumor suppression and emphasizing the need for effective chemoprevention in these high-risk patients. Because the methyl ester of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO-Me) is a potent chemopreventive agent, we tested its efficacy in a highly relevant mouse model of BRCA1-mutated breast cancer. Beginning at 12 weeks of age, Brca1(Co/Co); MMTV-Cre;p53(+/-) mice were fed powdered control diet or diet containing CDDO-Me (50 mg/kg diet). CDDO-Me significantly (P < 0.05) delayed tumor development in the Brca1-mutated mice by an average of 5.2 weeks. We also observed that levels of ErbB2, p-ErbB2, and cyclin D1 increased in a time-dependent manner in the mammary glands in Brca1-deficient mice, and CDDO-Me inhibited the constitutive phosphorylation of ErbB2 in tumor tissues from these mice. In BRCA1-deficient cell lines, the triterpenoids directly interacted with ErbB2, decreased constitutive phosphorylation of ErbB2, inhibited proliferation, and induced G(0)-G(1) arrest. These results suggest that CDDO-Me has the potential to prevent BRCA1-mutated breast cancer.

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Available from: Karen T Liby, Jul 25, 2014
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    • "Natural triterpenoids are abundantly found in marine sources, for example marine sponges, sea cucumbers, or marine algae [103], and have antiproliferative, antiangiogenic, anti-inflammatory, and pro-apoptotic activity [104]. CDDO esters and CDDO-Me have been shown to delay ER-negative mammary tumor formation in animal studies (Table 1) [70, 105]. "
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    ABSTRACT: Preventing breast cancer is an effective strategy for reducing breast cancer deaths. The purpose of chemoprevention (also termed preventive therapy) is to reduce cancer incidence by use of natural, synthetic, or biological agents. The efficacy of tamoxifen, raloxifene, and exemestane as preventive therapy against estrogen-receptor (ER)-positive breast cancer is well established for women at increased risk for breast cancer. However, because breast cancer is a heterogeneous disease, distinct preventive approaches may be required for effective prevention of each subtype. Current research is, therefore, focused on identifying alternative mechanisms by which biologically active compounds can reduce the risk of all breast cancer subtypes including ER-negative breast cancer. Promising agents are currently being developed for prevention of HER2-positive and triple-negative breast cancer (TNBC) and include inhibitors of the ErbB family receptors, COX-2 inhibitors, metformin, retinoids, statins, poly(ADP-ribose) polymerase inhibitors, and natural compounds. This review focuses on recent progress in research to develop more effective preventive agents, in particular for prevention of ER-negative breast cancer.
    Current Breast Cancer Reports 06/2014; 6(2):96-109. DOI:10.1007/s12609-014-0144-1
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    • "In a mouse model in which deletion of the BRCA1 gene (breast cancer associated gene 1) is combined with a mutation in a single allele in the p53 tumor suppressor gene, CDDO-Me significantly delays tumor development [20]. Beginning at 12 weeks of age, Brca1Co/Co; MMTV-Cre;p53+/- mice were fed powdered control diet or diet containing CDDO-Me. "
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    ABSTRACT: Solid cancer remains a major cause of death in the world. As limited treatment options are currently available to patients with solid cancer, novel preventive control and effective therapeutic approaches are considered to be reasonable and decisive measures to combat this disease. The plant-derived triterpenoids, commonly used for medicinal purposes in many Asian countries, poses various pharmacological properties. A large number of triterpenoids exhibit cytotoxicity against a variety of cancer cells, and cancer preventive, as well as anticancer efficacy in preclinical animal models. To improve antitumor activity, some synthetic triterpenoid derivatives have been synthesized, including cyano-3,12-dioxooleana-1,9(11)- dien-28-oic (CDDO), its methyl ester (CDDO-Me), and imidazolide (CDDO-Im) derivatives. In this review, we will critically examine the current preclinical evidences of cancer preventive and therapeutic activity about one of the synthetic triterpenoids, CDDO-Me. Both in vitro and in vivo effects of this agent and related molecular mechanisms are presented.
    Molecular Cancer 02/2014; 13(1):30. DOI:10.1186/1476-4598-13-30 · 4.26 Impact Factor
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    • ". Immunohistochemistry was performed as previously described [14]. An antibody against CYP7A1 was purchased from Abcam (Cambridge, MA). "
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